The present invention relates to 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives that are useful as a medicament. In particular, it relates to novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives which exhibit treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are roughly classified into two types: the xe2x80x9cionotropic typexe2x80x9d, in which the receptor has an ion channel type structure, and the xe2x80x9cmetabotropic typexe2x80x9d, in which the receptor is coupled to G-proteins (Science, 258, 597-603, 1992). In addition, ionotropic receptors are classified pharmacologically into three types: NMDA, xcex1-amino-3-hydroxy-5-methyl isoxazole-4-propionate (AMPA), and kainate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; and Neuropharmacol., 34, 1-26, 1995).
The metabotropic glutamate receptors are classified pharmacologically into three groups. Of these, group 2 (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13 (1993)), and for this reason, it is suggested that the compounds acting on group 2 metabotropic glutamate receptors should be useful for the treatment or prevention of acute and chronic psychiatric disorders and neurological diseases.
An object of the present invention is to provide a medicament acting on group 2 metabotropic glutamate receptors, which has the treatment effects and/or prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or on neurological diseases such as drug dependence, cognitive disorders, Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
As a result of a diligent research with regard to 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and ester derivatives thereof, the present inventors discovered novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and ester derivatives thereof, which act on group 2 metabotropic glutamate receptors, and have consequently, completed the present invention.
One mode of the present invention relates to a 2-amino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative represented by the formula [I]: 
(wherein, R1 and R2 are the same or different, and each represents a hydrogen atom, a C1-10 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl C1-6 alkyl group, an aryl group, an aryl C1-6 alkyl group, a C1-6 alkoxy C1-6 alkyl group, an C1-6 hydroxyalkyl group, a C1-6 alkylthio C1-6 alkyl group, a C1-6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group;
in R3 and R4, when R3 is a hydroxyl group, R4 is a hydrogen atom; alternatively, R3 and R4 together form a Cxe2x80x94C single bond),
a pharmaceutically acceptable salt thereof.
Another mode of the present invention relates to a medicament comprising the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient, and in particular, relates to an agent for treating or preventing psychiatric disorders or neurological diseases, as well as relates to a group 2 metabotropic glutamate receptor modulator.
Another mode of the present invention relates to use of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, for the manufacture of a group 2 metabotropic glutamate receptor modulator, and for the manufacture of an agent for treating and/or preventing psychiatric disorders and/or neurological diseases.
The terms used in the present invention are defined below. In the present invention, xe2x80x9cCn-mxe2x80x9d means that the group following the xe2x80x9cCn-mxe2x80x9d has a number of carbon atoms n to m.
The C1-10 alkyl group means a straight-chain or branched-chain alkyl group, examples of which include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 2-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, a nonyl group, a decyl group, and the like.
The C3-8 cycloalkyl group means, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
The C3-8 cycloalkyl C1-6 alkyl group means, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like.
The aryl group means a phenyl group, a naphthyl group, or the like, and preferably means a phenyl group. The aryl C1-6 alkyl group means a straight-chain or branched-chain C1-6 alkyl group substituted with at least one aryl group, and preferably at least one phenyl group. Examples thereof include, for example, a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, a 2-phenylethyl group, and the like.
The C1-6 alkoxy C1-6 alkyl group means a group having a combined structure of a C1-6 alkoxy group and a C1-6 alkyl group. The C1-6 alkoxy group means a straight-chain or branched-chain alkoxy group, examples of which include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group, or the like. Therefore, examples of the C1-6 alkoxy C1-6 alkyl group include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, an isopropoxyethyl group, a butoxyethyl group, an isobutoxyethyl group, a pentyloxyethyl group, an isopentyloxyethyl group, and the like.
The C1-6 hydroxyalkyl group means a C1-6 alkyl group substituted with at least one hydroxyl group. Therefore, examples of the C1-6 hydroxyalkyl group include a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and the like.
The C1-6 alkylthio C1-6 alkyl group means a group having a combined structure of a C1-6 alkylthio group and a C1-6 alkyl group. The C1-6 alkylthio group means a straight-chain or branched-chain alkylthio group, examples of which include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a t-butylthio group, a pentylthio group, an isopentylthio group, and the like. Therefore, examples of the C1-6 alkylthio C1-6 alkyl group include a methylthiomethyl group, a 2-methylthioethyl group, and the like.
The C1-6 mercaptoalkyl group means a C1-6 alkyl group substituted with at least one mercapto group. Therefore, examples of the C1-6 mercaptoalkyl include a 2-mercaptoethyl group, a 3-mercaptopropyl group, a 2,3-dimercaptopropyl group, and the like.
In addition, a pharmaceutically acceptable salt in the present invention refers to, for example, a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, or phosphoric acid; a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, or benzenesulfonic acid; a salt with an amine such as trimethylamine, or methylamine; or a salt with a metal ion such as sodium ion, potassium ion, or calcium ion.
The compounds represented by the formula [I] have four or five asymmetric carbon atoms. Therefore, the compounds of the present invention can be present as optically active substances, enantiomers thereof, or an enantiomer mixture such as racemic body. That is, the compounds of the present invention include all the optically active substances of the compounds represented by the formula [I], enantiomers thereof, an enantiomer mixture such as racemic body, and a diastereomer mixture. In the formula [I], the compounds, wherein R3 represents a hydroxyl group, and R4 represents a hydrogen atom, are preferable. Furthermore, in the formula [I], the compounds, wherein R1, R2, and R4 represent a hydrogen atom, and R3 represents a hydroxyl group, are more preferable. (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid is particularly preferable. In addition, the compounds of the present invention can be present as various solvates, and hydrates are preferable from the standpoint of applicability as a medicament.
In addition, in the formula [I], if both of R1 and R2 or one of R1 and R2 do not represent a hydrogen atom, that is, in the case of the ester derivatives, the ester derivatives do not act on group 2 metabotropic glutamate receptors. However, the ester derivatives are subjected to hydrolysis in vivo, and as a result, they are converted into the carboxylic acids which can act on group 2 metabotropic glutamate receptors. Therefore, the ester derivatives function as prodrugs, and for this reason, they are extremely useful compounds.
The compounds of the formula [I] can be produced according to the preparation methods described below (in the following reaction schemes, R1, R2, R3, and R4 have the same meanings as described above). 
Step 1: First, Compound (1) is transformed into Compound (2) by means of the reaction with a trifluoromethanesulfonylation agent, such as trifluoroacetic anhydride, N-phenyl-bis(trifluoromethanesulfonimide), or the like, in the presence of a base in an inert solvent.
In this step, as the inert solvent, for example, hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; a mixture of these solvents; or the like can be employed.
In addition, as the base, for example, amines such as triethylamine, N-methylmorpholine, diisopropylethylamine, and pyridine; inorganic bases such as potassium hydride and sodium hydride; metal amides such as lithium diisopropylamide and potassium bis(trimethylsilyl)amide; or metal alcholates such as sodium methoxide and potassium t-butoxide can be employed.
Step 2: Next, Compound (2) is transformed into Compound (3) by means of the reaction with carbon oxide and R2OH in the presence of a transition metal catalyst, and in the presence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, and pyridine, or of inorganic bases such as potassium carbonate and sodium hydrogencarbonate, in an inert solvent (see J. Org. Chem. 57, 5979 (1992)).
In this step, the transition metal catalyst means, for example, a palladium (0) reagent, and can be prepared in the reaction system by employing, for example, a divalent palladium such as palladium (II) acetate, and a ligand such as triphenylphosphine or 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP). In addition, a palladium (0) catalyst such as tetrakis(triphenylphosphine) palladium (0) can be directly employed.
In addition, as the inert solvent, for example, hydrocarbon type solvents such as benzene, toluene, and hexane; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; a mixture of these solvents; or the like can be employed.
Step 3: Compound (3) is oxidized to synthesize a diol derivative, Compound (4), by means of, for example, a common diol-formation reaction with osmium tetraoxide (see Oxidations in Organic Chemistry, written by Milos Hudlicky) or a chiral cis-dihydroxylation reaction of Sharpless with AD-mix as a reagent (Sharpless AD) described in Tetrahedron Asymmetry, 4(1), 133 (1993), which is incorporated herein by reference.
In this step, as the inert solvent, for example, hydrocarbon type solvents such as benzene, toluene, and hexane; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; acetone; N,N-dimethylformamide; water; a mixture of these solvents; or the like can be employed.
Step 4: Compound (4) is reacted with thionyl chloride in the presence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, and pyridine, or of inorganic bases such as potassium carbonate and sodium hydrogencarbonate, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; a mixture of these solvents; or the like.
Subsequently, the reaction product is oxidized to synthesize Compound (5), in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; acetone; water; a mixture of these solvents; or the like, by employing a common oxidant such as hydrogen peroxide, OXONE(copyright) (registered trademark of E.I. Dupont De Nemours and Company), or ruthenium trichloride-sodium metaperiodate (see Oxidations in Organic Chemistry, written by Milos Hudlicky).
Step 5: Compound (5) is transformed into Compound (6) by means of the reaction with, for example, sodium azide in an inert solvent, examples of which include ether type solvents such as tetrahydrofuran; ketones such as acetone; N,N-dimethylformamide; water; a mixture of these solvents; or the like. 
Step 6: Compound (6) is transformed into Compound (7) by means of the reaction with a trifluoromethanesulfonylation agent such as trifluoroacetic anhydride, N-phenyl-bis(trifluoromethanesulfonimide), or the like, in the presence of amines such as triethylamine, diisopropylethylamine, and pyridine, or of inorganic bases such as potassium carbonate and sodium hydrogencarbonate, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; a mixture of these solvents; or the like.
Step 7: Compound (7) is transformed into Compound (8) by means of the reaction with amines such as triethylamine, diisopropylethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene; inorganic bases such as potassium carbonate, sodium hydrogencarbonate, and sodium hydride; or metal alcholates such as sodium methoxide and potassium t-butoxide, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; a mixture of these solvents; or the like.
Step 8: Compound (8) is transformed into Compound (9) by means of a Staudinger reaction with, for example, triethyl phosphite or triphenylphosphine (see Bull. Chem. Soc. Fr., 815 (1985)) or by means of a common reduction reaction of an azide group, utilizing lithium aminoborohydride or the like, described in Reductions in Organic Synthesis, written by Ahmed F. Abdel-Magid, which is incorporated herein by reference, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, and hexane; halogen type solvents such as dichloromethane and chloroform; ether type solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; acetonitrile; acetone; water; a mixture of these solvents; or the like.
Step 9: Furthermore, Compound (9) can be transformed into Compound (10) which is the compound of the present invention, by simultaneously or successively converting R1 and R2 of the ester moieties of Compound (9) into hydrogen atoms by means of a common hydrolysis described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, written by THEODORA W. GREENE and PETER G. M. WUTS, which is incorporated herein by reference. 
Step 10: On the other hand, Compound (6) can be transformed into Compound (11) which is the compound of the present invention, by means of hydrogenation in the presence of a metal catalyst such as palladium/carbon or palladium black, in an inert solvent, examples of which include alcohols such as ethanol and methanol; esters such as ethyl acetate; N,N-dimethylformamide; water; a mixture thereof; or the like. In this step, when R1 and R2 represent, for example, a benzyl group, or the like, R1 and R2 are hydrogenated during the hydrogenation of the azide group, so that R1 and R2 can be converted into hydrogen atoms.
Step 11: Subsequently, by converting the ester moieties of Compound (11) into carboxylic acids by means of a common hydrolysis described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, written by THEODORA W. GREENE and PETER G. M. WUTS, which is incorporated herein by reference, Compound (12) which is the compound of the present invention can be synthesized.
The compounds of the present invention can be formulated into pharmaceutical preparations by combining with one or more pharmaceutically acceptable carriers, excipients, and/or diluents. As examples of the carriers, excipients, and diluents described above, mention may be made of water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, arginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerol, and oils such as sesame oil, olive oil, and soybean oil.
The compounds of the present invention, after being mixed with the carriers, excipients, or diluents, and if necessary, being mixed with additives such as commonly employed fillers, binders, disintegrants, pH regulators, and solubilizers, can be formulated, by means of common formulation technology, into drugs for oral or parenteral administration, especially as group 2 metabotropic glutamate receptor modulators, in the form of, for example, tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, and skin plasters. The compounds of the present invention can be administered orally or parenterally to an adult patient in a quantity of 0.01 to 500 mg in a single dose or in divided doses per day, and can be preferably administered orally in view of facility for use and pharmaceutical effects. The dosage can be increased or decreased as appropriate in consideration of the type of disease to be treated and the age, weight, and symptoms of the patient.